It is believed that 5-hydroxytryptamine (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its metabolite 5-hydroxyindole acetic acid are excreted in the urine during most attacks. Further, plasma and platelet 5-HT concentrations fall rapidly at the onset of an attack and remain low whilst the headache persists. Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would be of use in the treatment of migraine (J. R. Fozard, International Headache Congress 1980) reported in Advances in Neurology, Vol. 33, Raven Press, New York 1982).
The known migraine propylactic drugs methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but are all 5-HT D-receptor antagonists at the doses used clinically for the treatment of migraine and all reduce 5-HT transmission.
The reduction of 5-HT transmission also can be produced by the blockade of the enzyme tryptophan hydroxylase, the initial step in 5-HT biosynthesis and a known tryptophan hydroxylase inhibitor, para-chlorophenylalanine, has been shown to be beneficial in the treatment of migraine (F. Sicuteri, Headache 10, 124(1970)). However, the continued use of para-chlorophenylalanine in the treatment of migraine has been precluded because of its untoward toxic effects.
it is an object of the present invention to provide compounds which will reduce the activity of tryptophan hydroxylase by blocking the depolarization-induced induction of the enzyme. It is believed that the blockade of the induction of the enzyme diminishes the functional pool of 5-HT and thereby reduces 5-HT transmission and hence reduces, or eliminates, migraine attacks.
It has been disclosed in U.S. Pat. No. 3,963,729, of which we are the Inventors, that inter alia compounds of the following Formula I have central nervous system, especially antidepressant, activity: ##STR2## wherein:
R.sub.1 represents methoxy, ethoxy or hydroxy,
R.sub.2 represents methoxy, ethoxy, hydroxy or hydrogen;
each R.sub.3 independently represents methyl or ethyl; and
n represents 2 or 3.
The specific examples of compounds of Formula I stated in the U.S. patent are 3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxo pipe ridine and 3-(3'-methoxyphenyl)-3-(2"-N,N-dimethyl aminoethyl)-4,4-dimethyl-2,6-dioxopiperidine.
It has now been found that the compounds of Formula I unexpectedly reduce the activity of tryptophan hydroxylase by blocking the depolarization induced induction of the enzyme and hence are of potential use in the prophylactic treatment of migraine.